Sarcomas are neoplastic malignancies that typically arise in tissues of mesenchymal origin. The identification of novel molecular mechanisms leading to sarcoma formation and the establishment of new therapies has been hampered by several critical factors. First, this type of cancer is rarely observed in the clinic with fewer than 15,000 newly cases diagnosed each year in the United States. Another complicating factor is that sarcomas are extremely heterogeneous as they arise in a multitude of tissues from many different cell lineages e.g. bone osteosarcoma, fat liposarcoma, and muscle myosarcoma. The scarcity of clinical samples coupled with its inherent heterogeneity creates a challenging experimental environment for clinicians and scientists. Faced with these challenges, there has been extremely limited advancement in treatment options available to patients as compared to other cancers. In order to glean insight into the pathobiology of sarcomas, scientists are now using in vivo mouse models whose genomes have been specifically tailored to carry gene deletions, gene amplifications, and point mutations commonly observed in human sarcomas. The use of these model organisms has been successful in increasing our knowledge and understanding of how alterations in relevant oncogenic, tumor suppressive, and signaling pathways directly impact sarcomagenesis. It is the goal of many in the biological community that the use of these mouse models will serve as powerful in vivo tools to further our understanding of sarcomagenesis and potentially identify new therapeutic strategies.